Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial.
Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial.
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DOI：
10.1053/j.gastro.2018.03.029
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发表时间：
2018-07
期刊：
影响因子：
29.4
通讯作者：
June CH
中科院分区：
文献类型：
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作者：
Beatty GL;O'Hara MH;Lacey SF;Torigian DA;Nazimuddin F;Chen F;Kulikovskaya IM;Soulen MC;McGarvey M;Nelson AM;Gladney WL;Levine BL;Melenhorst JJ;Plesa G;June CH
胰腺导管腺癌（PDAC）对T细胞介导的免疫疗法具有抗性。我们设计T细胞瞬时表达编码间皮素特异性嵌合抗原受体（CAR）的mRNA，间皮素是PDAC细胞过度表达的蛋白质。我们进行了一项1期研究，以评估在6名化疗难治性转移性PDAC患者中使用自体间皮素特异性CAR T细胞（CARTmeso细胞）进行过继细胞治疗的安全性和有效性。患者每周静脉内给予CARTmeso细胞3次，持续3周。没有患者发生细胞因子释放综合征或神经系统症状，也没有剂量限制性毒性。2例患者病情稳定，无进展生存期为3.8和5.4个月。我们使用FDG-正电子发射断层扫描/计算机断层扫描成像来监测单个肿瘤病变的代谢活性体积（MAV）。3例患者的总MAV保持稳定，1例活检证实间皮素表达的患者降低了69.2%;在该患者中，与基线相比，所有肝脏病变在1个月时的FDG摄取完全降低，尽管对原发性PDAC没有影响。输注后在患者血液中检测到瞬时CAR表达，并导致新的免疫球蛋白G蛋白扩增。我们的结果为mRNA CARTmeso细胞的潜在抗肿瘤活性以及PDAC对免疫应答的抗性提供了证据。关键词：免疫应答异质性，免疫治疗，抗肿瘤免疫，胰腺癌治疗
Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell mediated immunotherapy. We engineered T cells to transiently express an mRNA encoding a chimeric antigen receptor (CAR) specific for mesothelin—a protein that is over-expressed by PDAC cells. We performed a phase 1 study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used FDG-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared to baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients’ blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential anti-tumor activity of mRNA CARTmeso cells, as well as PDAC resistance to the immune response. Keywords: immune response heterogeneity, immune therapy, anti-tumor immunity, pancreatic cancer treatment
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影响因子：
45.3
作者：
Le, Dung T.;Wang-Gillam, Andrea;Jaffee, Elizabeth M.
通讯作者：
Jaffee, Elizabeth M.
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
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作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM
影响因子：
13.5
作者：
Beatty, Gregory L.;O'Hara, Mark
通讯作者：
O'Hara, Mark
影响因子：
11.2
作者：
Pastan I;Hassan R
通讯作者：
Hassan R
影响因子：
64.8
作者：
通讯作者：
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